Chlamydia trachomatis is the cause for the most common bacterial sexually transmitted disease in the United States. Commonly referred to as a silent epidemic, C. trachomatis infections in women are frequently asymptomatic, and often go unnoticed and untreated. The infection can persist for years and chronic infections ultimately result in pelvic inflammatory disease, ectopic pregnancies, and infertility. Whereas some individuals clear infections with C. trachomatis successfully, others fail to do so. The heterogeneity in the ability of individuals to clear C. trachomatis infections suggests a genetic component underlying the relative resistance to C. trachomatis infections. Our previous unbiased genetic approach led to the identification of Immunity Related GTPase (IRGs) as critical mediators of host resistance to C. trachomatis infections in mice. IRGM proteins, a subfamily of IRGs, exist both in mice and humans and human IRGM can provide resistance to C. trachomatis infections. Importantly, the human IRGM locus is highly polymorphic and has been associated with increased susceptibility to infectious and autoinflammatory diseases. Therefore, the IRGM locus is a strong candidate to be a critical determinant in shaping the outcome of C. trachomatis infections. We are pursuing three interrelated aims to understand how IRGM proteins provide resistance to C. trachomatis infections in mice and humans. (1) We will determine how IRGM proteins orchestrate cell-autonomous resistance pathways targeting C. trachomatis (2) We will define which human IRGM isoforms are responsible for providing resistance to C. trachomatis and whether genetic variants of the human IRGM gene differ in their ability to provide cell-autonomous resistance to C. trachomatis. (3) We will describe IRGM-dependent immune response to C. trachomatis in vivo using novel mouse models. It is hoped that these studies will not only substantially advance our understanding of host responses to C. trachomatis but also facilitate the development of novel immunological and pharmacological strategies to prevent chronic infections with C. trachomatis.